It is currently known that topical or transdermal delivery systems for the administration of drugs offer several advantages over oral delivery of the same drugs. Generally, the advantages of topical or transdermal delivery of drugs relate to pharmacokinetics. More specifically, one common problem associated with the oral delivery of drugs is the occurrence of peaks in serum levels of the drug, which is followed by a drop in serum levels of the drug due to its elimination and possible metabolism. Thus, the serum level concentrations of orally administered drugs have peaks and valleys after ingestion. These highs and lows in serum level concentrations of drug often lead to undesirable side effects.
In contrast, topical and transdermal delivery of drugs provides a relatively slow and steady delivery of the drug. Accordingly, unlike orally administered drugs, the serum concentrations of topically or transdermally delivered drugs are substantially sustained and do not have the peaks associated with oral delivery.
The sustained serum concentrations associated with topical or transdermal drug delivery avoids the systemic side effects of oral administration of drugs. Specifically, first pass metabolism of the drug by the liver is circumvented by utilizing transdermal or topical delivery vehicles for the administration of drugs.
The advantages of topical or transdermal drug delivery vehicles as compared to oral drug delivery is generally well-known for various drugs. For instance, Powers et al. demonstrated advantages of transdermal estradiol over oral estradiol. See, Powers M S, Schenkel L, Darkey P E, Good W R, Balestra J C, Place V A; “Pharmacokinetics and pharmacodynamics of transdermal dosage forms of 17β-estradiol: Comparison with conventional oral estrogens for hormone replacement,” Am. J. Obstet. Gynecol., 1985; 152:1099. Van Seventer et al reported that patient assessment favored transdermal fentanyl treatment over sustained release morphine in terms of a significantly lower rate of troublesome side-effects and less interruption of daily activities. See, Van Seventer R, Smit J M, Schipper R M, Wicks M A, Zuurmond W W, “Comparison of TTS-fentanyl with sustained-release oral morphine in the treatment of patients not using opioids for mild-to-moderate pain.”; Curr Med Res Opin. 2003;19(6):457-69.
Additionally, Heyneman et al. reported that topically applied nonsteroidal anti-inflammatory drugs (NSAIDs) have a superior safety profile to oral formulations. Also reported was that adverse effects, secondary to topical NSAID application, occur in approximately 10 to 15% of patients and are primarily cutaneous in nature (rash and pruritus at site of application); gastrointestinal adverse drug reactions are rare with topically applied NSAIDs, compared with a 15% incidence reported for oral NSAIDs. See, Heyneman C A, Lawless-Liday C, Wall G C, “Oral versus topical NSAIDs in rheumatic diseases: a comparison”, Drugs. September 2000;60(3):555-74.
Barrett et al. found that the plasma concentrations of selegiline after transdermal application was more than 50-fold greater than that obtained with oral selegiline. This increase in systemic plasma concentrations of selegiline at the expense of metabolites formation that is reduced to less than 70% of that obtained orally is hypothesized to be of therapeutic value in patients with a variety of neurodegenerative and psychiatric disorders. See, Barrett J S, Hochadel T J, Morales R J, Rohatagi S, DeWitt K E, Watson S K, DiSanto A R; “Pharmacokinetics and Safety of a Selegiline Transdermal System Relative to Single-Dose Oral Administration in the Elderly.”; Am J Ther. October 1996;3(10):688-698.
Likewise, it is also generally known that there exists a significant decrease in adverse effects associated with the transdermal delivery of oxybutynin. Oral oxybutynin has been indicated for the relief of symptoms of bladder instability associated with voiding in patients with uninhibited neurogenic or reflex neurogenic bladder, i.e., urgency, frequency, urinary leakage, urge incontinence, and dysuria.
Oxybutynin has been found to have a direct antispasmodic effect on smooth muscle and inhibits the muscarinic action of acetylcholine on smooth muscle, but exhibits only one-fifth of the anticholinergic activity of atropine detrusor muscle (effect observed in rabbits), and four to ten times its antispasmodic activity. Oxybutynin has not been found to possess blocking effects at skeletal neuromuscular junctions or autonomic ganglia (antinicotinic effects).
Moreover, oxybutynin has been found to relax bladder smooth muscle. In patients with conditions characterized by involuntary bladder contractions, cystometric studies have demonstrated that oxybutynin increases bladder (vesical) capacity, diminishes the frequency of uninhibited contractions of the detrusor muscle, and delays the initial desire to void. Oxybutynin thus decreases urgency and the frequency of both incontinent episodes and voluntary urination. It has also been reported that antimuscarinic activity resides predominantly in the R-isomer.
Adverse reactions associated with oxybutynin therapy, however, may include cardiovascular manifestations such as palpitations, tachycardia or vasodilatation; dermatologic manifestations such as decreased sweating, rash; gastrointestinal/genitourinary manifestations such as constipation, decreased gastrointestinal motility, dry mouth, nausea, urinary hesitance and retention; nervous system manifestations such as asthenia, dizziness, drowsiness, hallucinations, insomnia, restlessness; opthalmic manifestations such as amblyopia, cycloplegia, decreased lacrimation, mydriasis. Most common side effects associated with oral oxybutynin encompasses dry mouth, dizziness, blurred vision, and constipation. These adverse experiences may be uncomfortable enough to persuade the patient to discontinue treatment.
In a study which compared transdermal delivery and oral delivery of oxybutynin, a substantially lower fluctuation in oxybutynin and its metabolite N-desethyloxybutynin plasma concentrations was demonstrated with the transdermally administered oxybutynin. Additionally, reduced N-desethyloxybutynin formation, and greater saliva production during the dosing period was reported compared with oral oxybutynin administration. Moreover, lower incidences of dry mouth in patients with overactive bladder were reported. See, Appel R A, Chancellor M B, Zobrist R H, Thomas H, Sanders S W, “Pharmacokinetics, Metabolism, and Saliva Output during Transdermal and Extended-Release Oral Oxybutynin Administration in Healthy Subjects”, Mayo Clin. Proc. 2003;78: 696-702.
Moreover, Dmochowsky et al. confirmed the improvement of overactive bladder symptoms and quality of life (dry mouth incidence reduction) in patients treated with transdermal oxybutynin compared to oral oxybutynin therapy. See, Dmochowski R R, Davila G W, Zinner N R, Gittelman M C, Saltzstein D R, Lyttle S, Sanders S W; For The Transdermal Oxybutynin Study Group.; “Efficacy and safety of transdermal oxybutynin in patients with urge and mixed urinary incontinence”, The Journal of Urology, Vol. 168, 580-586, Aug. 2002. Thus, it can be easily seen that transdermal delivery of oxybutynin has been shown to be more advantageous, as well as preferred over oral delivery of oxybutynin.
As known in the art, the transdermal administration of drugs has certain drawbacks associated with drug penetration across the dermal barrier. Skin is a structurally complex multilayered organ with a total thickness of 2-3 mm. Thus, penetration of drugs to skin is only efficient if the skin barrier is overcome. The main source of resistance to penetration and permeation through the skin is the stratum corneum layer of the skin, which is also known as the “horny layer.”
The stratum corneum consists of layers of highly flattened keratin-filled cells and is of thin layers of dense, approximately 10-15 microns thick over most of the body. Thus the permeation rate of many drugs through the skin is extremely low. Thus, there is continued interest in the development of strategies to alter the skin barrier to percutaneous absorption of compounds.
Reduction of the skin barrier function is predicted to increase the therapeutic efficacy of dermatological formulation and transdermal devices, by obtaining significant improvements in the kinetics and/or extent of percutaneous absorption. In order to increase the rate at which a drug penetrates through the skin, different strategies have been followed, involving the use of either a physical penetration enhancer (iontophoresis, sonophoresis, heating) or a chemical penetration enhancer, administered along with the drug or in some cases before the drug is applied on the skin (“pre-treatment”).
Generally, suitable permeation enhancers which promote the percutaneous absorption of a number of drugs is known. These permeation enhancers have been classified according to their mechanism of action. See, Sinha V R, Kaur M P, “Permeation Enhancers for Transdermal Drug Delivery,” Drug Dev Ind Pharm. Nov. 2000;26(11):1131-40.
Although permeation enhancers have become widely used in transdermal or topical delivery of drugs, one problem is that no specific permeation enhancer may be considered as suitable for all drugs, as demonstrated above. Moreover, the selection of the most efficient permeation enhancer for a particular drug relies on empirical techniques, the applicability of which is far from universal, and the results are too unpredictable. For example, the selection of an appropriate permeation enhancer will depend on many parameters including:                (1) The specific drug to be administered. A permeation enhancer identified for one specific drug may not be efficient with another drug;        (2) The permeation enhancer concentration. The enhancement effect may be optimal at a given concentration of the permeation enhancer, and may be lowered or even negative under or above this concentration;        (3) The vehicle or carrier. A permeation enhancer may be efficient in a aqueous vehicle for instance, while not efficient in an organic vehicle; and        (4) The components of the system. The permeation enhancer may interact with the drug itself, and thus considerably alter the characteristics and the stability of the drug, or with polymers, antioxidants, and the like.        
Some approaches to the selection of enhancers formulated into topical systems have been published by Pfister, Yum and Ghosh, “Transdermal and Topical Drug Delivery Systems,” Chapter 11: “Chemical means of transdermal drug permeation enhancement,” (Interpharm Press, Inc. 1997). However, as demonstrated in a considerable amount of studies, the main principle governing the selection of a permeation enhancer is “trial and error.” Accordingly, an optimized transdermal formulation can only be achieved after conducting numerous experiments.
Various permeation enhancers have been reported for transdermal or topical delivery of oxybutynin. For example, U.S. Pat. No. 5,411,740, U.S. Pat. No. 5,500,222, U.S. Pat. No. 5,614,211, each disclose monoglyceride or a mixture of monoglycerides of fatty acids as the preferred permeation enhancer for an oxybutynin transdermal therapeutic system. U.S. Pat. No. 5,736,577 describes a pharmaceutical unit dosage form for transdermal administration of (S)-oxybutynin comprising a permeation enhancer. U.S. Pat. No. 5,834,010 and U.S. Pat. No. 6,555,129 both disclose triacetin as a permeation enhancer for oxybutynin. U.S. Pat. No. 5,747,065 discloses monoglycerides and lactate esters as a permeation enhancing mixture for oxybutynin.
Moreover, U.S. Pat. No. 5,843,468 describe a dual permeation enhancer mixture of lauryl acetate and a glycerol monolaurate for transdermal administration of oxybutynin. U.S. Pat. No. 6,004,578 disclose permeation enhancers selected from the group consisting of alkyl or aryl carboxylic acid esters of polyethyleneglycol monoalkyl ether, and polyethyleneglycol alkyl carboxymethyl ethers for a transdermal matrix drug delivery device comprising oxybutynin. Meanwhile, U.S. Pat. No. 6,267,984 discloses skin permeation enhancer compositions comprising a monoglyceride and ethyl palmitate for transdermal delivery of oxybutynin. U.S. Pat. No. 6,562,368 discloses the use of hydroxide-releasing agent to increase the permeability of skin or mucosal tissue to transdermally administered oxybutynin. As mentioned above, currently, the approach to finding a suitable permeation enhancer for a particular drug is through trial and error.
Urea is a natural substance and a final metabolite of proteins in the body. The value of urea in pharmaceutical and cosmetic preparations has been recognized since the early days of folk medicine, e.g., urea aids in debridement, dissolves the coagulum and promotes epithelialization when used in a concentration of approximately 10-15 percent; at higher concentrations, e.g. above 40 percent, urea is proteolytic and therefore, is commonly used for the treatment of nail destruction and dissolution, urea is also used as an osmotic diuretic.
One remarkable property of urea is the increased water-holding capacity of the stratum corneum in the presence of urea. Urea is mildly keratolytic and increases water uptake in the stratum corneum. This gives the stratum corneum a high water-binding capacity. Accordingly, urea is often used as a skin moisturizer.
Urea is also generally known as a permeation enhancer for certain drugs. However, the percutaneous absorption enhancement by urea is strongly dependent on the cosolvents used. For example, Kim et al. observed that the penetration of ketoprofen was enhanced in the presence of urea in aqueous solutions, whereas in propylene glycol or propylene glycol-ethanol mixtures no enhancement was reported. Moreover, Kim found that the addition of high amounts of urea increases the diffusivity of ketoprofen.
A similar synergetic effect was also demonstrated by Lu et al, who demonstrated that the absorption of leuprolide from human cadaver skin, hairless mouse skin, and shed snake skin was enhanced in the presence of urea and terpenes. These enhancers alone, i.e., without solvent, however, did not significantly enhance permeation. Lu M Y, Lee D. Rao G S, “Percutaneous absorption enhancement of leuprolide,” Pharm. Res. Dec. 1992;9 (12): 1575-9. Similar to the above cited study, the incorporation of urea significantly increases diffusivity of the drug. This kind of solvent dependency was also cited by Williams in “Percutaneous Penetration Enhancers”, chapter 10.1: “Urea and its derivatives as penetration enhancers” eds. Smith et al., CRC Press, 1995.
Further, U.S. Pat. No. 5,696,164 and U.S. Pat. No. 6,042,845 both disclose a composition for anti fungal treatment of nails comprising urea in combination with a sulfhydryl containing amino acid or a derivative thereof as permeation enhancer. U.S. Pat. No. 4,996,193 discloses formulations for the topical application of cyclosporin to skin tissue in which urea is used as a permeation enhancer. U.S. Pat. No. 5,015,470 discloses cosmetic and pharmaceutical compositions for inducing, maintaining or increasing hair growth, which contain urea as permeation enhancer. U.S. Pat. No. 5,654,337 discloses a topical formulation for local delivery of anti-inflammatory or antineoplastic agents, in which urea is used to promote gel formation. U.S. Pat. Nos. 5,874,463 and in 6,300,369 both disclose a hydroxy-kojic acid skin peeling composition containing urea as skin-penetrating agent. U.S. Pat. No. 5,879,690 discloses compositions for the topical administration of catecholamines and related compounds to subcutaneous muscle tissue using percutaneous penetration enhancers including urea. U.S. Pat. No. 6,132,760 discloses a transdermal delivery device for testosterone containing urea as a monomer component of the copolymeric pressure sensitive skin adhesive. U.S. Pat. No. 6,162,419 discloses dermatological stabilized ascorbyl compositions containing permeation enhancers of urea or oleic acid.
Similarly, U.S. Pat. No. 6,214,374 discloses use of urea or urea derivatives as permeation enhancers for hormones. U.S. Pat. No. 4,699,777 discloses the synergistic action of combination of urea and 1-dodecyl-azacycloheptan-2-one on albuterol transdermal flux. U.S. Pat. No. 4,895,727 discloses a composition containing urea and a water-soluble zinc-containing compound inducing a reservoir effect in skin and mucous membranes so as to enhance penetration and retention and reduce transdermal flux of topically applied therapeutic and cosmetic pharmacologically active agents. U.S. Pat. No. 5,446,025 discloses a combination of urea, menthol, methyl salicylate and camphor as a cutaneous membrane penetration enhancing mixture for the percutaneous administration of leuprolide.
Urea is also uses as a soluble humectant, i.e., a water binding substance that is capable of retaining large amounts of water (relative to their weight) in the skin, thereby helping to keep the skin smooth and supple. Urea, along with certain amino acids, epidermal lipids and proteins, is known as a constituent of the natural moisturizing factor NMF, produced during the keratinisation process. See, Brian W. Barry “Dermatological Formulations: Percutaneous Absorption”, chapter 4, page 147, Marcel Dekker, ISBN: 0-8247-1729-5. Urea gets into the horny layer as an end product of the decomposition of the amino acid, arginine, which is a building block in proteins, during the keratinisation process. Urea represents 7% of the NMF in the horny layer. Urea penetrates and re-hydrates the stratum corneum.
The addition of urea to dermatological preparations is known to increase the penetration of corticosteroids, which are attributed to urea's ability to increase skin hydration after application. It also has anti-pruritic activity (stops itching) based on local anaesthetic effects.
The proteolytic characteristics of urea are also well recognized, where depending on the concentration, urea modifies the structure of amino-chains as well as of polypeptides. This is significant for skin moisturizing since a correlation exists between water content and amino acid content in skin—the drier the skin the lower the share of dissolved amino acids. Urea also helps in higher concentrations (10%) to reduce scales and calluses.
Numerous studies in which urea exhibited permeation enhancement effect is disclosed in Ghosh, Pfister and Yum in “Transdermal and Topical Drug Delivery Systems”, Chapter 11: “Chemical means of transdermal drug permeation enhancement” (Interpharm Press, Inc. 1997). The particular agents for which urea has been demonstrated to be a suitable permeation enhancer are shown below.
Enhancer andMembraneCompoundVehicleweight percenttypeaREbReferencesIndomethacinPatches(A) Urea: 15%Human(A) 2.5Kanikkhannan(B) Urea/octanol (1:1): 10%(B) 3.25et al. (1994)(C) Urea/PG (3:1): 20%(C) 3.75PetrolatumVarious cyclic ureas 5%(A) Shed snake(A) up to 2.0Wong et al.ointment(B) Hairless mouse(1989)KetoprofenAqueousUrea 20%Rat 1.5Kim et al.PGUrea 10% 3.1(1993)Ethanol/PG/H2OUrea 36% 3.5cLeuprolideHydrogelUrea 10%Human10Lu et al.Shed snake(1992)InsulinAqueous withUrea 10%Human2.11-3.80Rao and Misrasurfactants(1994)5-fluorouracilPropylene glycol(A) 1-dodecyl ureaHuman(C) up to 9.0Williams and(B) 1,3-didodecyl ureaBarry (1989)(C) 1,3-diphenyl ureaaIn vitro unless otherwise stated;bRelative Enhancement factor (RE) compared to control;cDiffusivities are compared;dNo data givenNote:PG = Propylene glycol
Interestingly, Ghosh, Pfister & Yum conducted a similar work on other chemical classes of penetration enhancers, i.e., hydrocarbons, alkanols and alkenols, acids, esters, alkyl amino esters, amides, sulfoxides, cyclodextrins, terpenes, pyrrolidones, Azone® and analogues, phospholipids, and surfactants. Examination of these comparative tables reveals that one particular active compound may present enhanced transdermal permeation when in contact with various permeation enhancers. For example, indomethacin for instance may be enhanced by urea, but also by nonane, 1-nonanol, oleic aciddecyl-(N,N-dimethylamino)isopropionate, tetrahydrothiophene-1-oxide and analogues, d-limonene, pyrrolidone analogues, Azone® and analogues.
As can be seen from the chart below, although different enhancers may be effective for enhancing penetration of particular drugs, the enhancement factor and efficacy can vary greatly.
Enhancement factoraPropylPropylDecylmethylDrugsmyristateoleateAzonesulfoxideProgesterone4.565.365.9611.04Estradiol9.3314.6220.1712.59Hydrocortisone4.575.0161.325.23Indomethacin3.774.6714.4915.67aEnhancement factor = (Normalized skin permeation rate) with enhancer/(Normalized skin permeation rate) without enhancer.See, Chien, “Developmental Concepts and Practice in Transdermal Therapeutic Systems” in Transdermal Controlled Systemic Medications, Marcel Dekker Inc., New York, 1987, pages 25-81, which is incorporated herein by reference.
In view of these results, it is known that a penetration enhancer increases the permeation of different compounds to different degree. For example, a particular permeation enhancer might be very adequate for a particular drug, but might not increase the permeability of a different drug. This is explained by the fact that transdermal permeability is mainly influenced by both the interaction of the permeants with the enhancers and by physicochemical properties of the permeants. Illustrative of these findings, Chien published the dependence of the enhancement factor for the skin permeation of progesterone on the alkyl chain length of saturated fatty acid in “Transdermal Controlled Systemic Medications.” He found major enhancement effect using caproic acid (C8), however the same author discloses in U.S. Pat. No. 5,145,682 that the better enhancer for estradiol is decanoic acid (C10). Thus, the efficacy of a skin penetration enhancer for a specific active agent is a function of the type, concentration, and how the penetration enhancer is released from the devices.
One problem in the art is that the concept of a “universal” enhancer for a transdermal penetration enhancement effect for any active agent or drug is nonexistent. Thus, selection of a permeation enhancer is ordinarily drug specific and determined by trial and error through experimentation. No general guidelines exist for ensuring success in selecting an appropriate enhancer for a specific drug to be delivered from a transdermal device (Hsieh 1994).
Further, the science of optimizing topical formulations is not predictive from one drug to another and permeation enhancers can produce a wide range of enhancement factors across drugs having different physicochemical properties. Rather, this is a process that requires extensive experimental work: adequate permeation rate across the skin can be achieved only by testing different types of compounds at different concentrations.
As a testament to this “trial and error” approach, below is a chart that illustrates various potential permeation enhancers that have been tested to promote the transdermal absorption of oxybutynin.
OxybutyninEnhancerAbsorbed dailySteady-concentrationconcentrationamountEnhancementstate fluxEnhancement[% w/w][% w/w][μg/cm2/24 h]Ratio ER[μg/cm2/h]Ratio ER3.0LA 139.150.861.780.763.0OAL 137.830.831.990.855.0EO 524.900.861.350.815.0DBP 524.320.841.180.715.0GML 535.000.951.700.845.0PGML 523.540.641.330.663.0EO 133.781.191.661.123.0EO 328.751.011.521.033.0AG 115.250.500.930.573.0AG 318.670.61n.a.n.a.3.0NMP 537.510.812.340.953.0NMP 1030.120.65n.a.n.a.LA: lauryl alcohol;OA: oleyl alcohol;EO: ethyl oleate;DBP: dibutyl phtalate;GML: glycerol monolaurate;PGML: propylene glycol monolaurate;AG: acetyl glycerol;NMP: N-methyl pyrrolidone.
As can be seen, the absorption rate, enhancement ratio, and steady state flux for these penetration enhancers vary greatly. Thus, there is a need for an improved topical or transdermal composition that adequately delivers anticholinergic agents, such as oxybutynin, and which enhances permeation of the anticholingeric agents across the dermal or mucosal barrier.